Sival Deborah A, Guerra Montserrat, den Dunnen Wilfred F A, Bátiz Luis F, Alvial Genaro, Castañeyra-Perdomo Agustín, Rodríguez Esteban M
Departments of Pediatrics Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
Brain Pathol. 2011 Mar;21(2):163-79. doi: 10.1111/j.1750-3639.2010.00432.x.
In human spina bifida aperta (SBA), cerebral pathogenesis [hydrocephalus, Sylvius aqueduct (SA) stenosis and heterotopias] is poorly understood. In animal models, loss of ventricular lining (ependymal denudation) causes SA stenosis and hydrocephalus. We aimed to investigate whether ependymal denudation also takes place in human foetal SBA. Considering that ependymal denudation would be related to alterations in junction proteins, sections through SA of five SBA and six control foetuses (gestational ages ranged between 37 and 40 weeks) were immunostained for markers of ependyma (caveolin 1, βIV-tubulin, S100), junction proteins (N-cadherin, connexin-43, neural cell adhesion molecule (NCAM), blood vessels (Glut-1) and astrocytes [glial fibrillary acidic protein (GFAP)]. In control foetuses, ependymal denudation was absent. In SBA foetuses different stages of ependymal denudation were observed: (i) intact ependyma/neuroepithelium; (ii) imminent ependymal denudation (with abnormal subcellular location of junction proteins); (iii) ependymal denudation (with protrusion of neuropile into SA, formation of rosettes and macrophage invasion); (iv) astroglial reaction. It is suggested that abnormalities in the formation of gap and adherent junctions result in defective ependymal coupling, desynchronized ciliary beating and ependymal denudation, leading to hydrocephalus. The presence of various stages of ependymal denudation within the same full-term SBA foetuses suggests continuation of the process after birth.
在开放性脊柱裂（SBA）患者中，大脑发病机制[脑积水、中脑导水管（SA）狭窄和异位症]尚未完全明确。在动物模型中，脑室衬里的缺失（室管膜剥脱）会导致SA狭窄和脑积水。我们旨在研究室管膜剥脱是否也发生在人类胎儿SBA中。考虑到室管膜剥脱可能与连接蛋白的改变有关，我们对5例SBA胎儿和6例对照胎儿（胎龄在37至40周之间）的SA切片进行了免疫染色，检测室管膜标记物（小窝蛋白1、βIV微管蛋白、S100）、连接蛋白（N-钙黏蛋白、连接蛋白-43、神经细胞黏附分子（NCAM））、血管（葡萄糖转运蛋白-1）和星形胶质细胞[胶质纤维酸性蛋白（GFAP）]。在对照胎儿中，未观察到室管膜剥脱。在SBA胎儿中，观察到了室管膜剥脱的不同阶段：（i）完整的室管膜/神经上皮；（ii）即将发生的室管膜剥脱（连接蛋白亚细胞定位异常）；（iii）室管膜剥脱（神经纤维束突入SA、玫瑰花结形成和巨噬细胞浸润）；（iv）星形胶质细胞反应。提示缝隙连接和黏附连接形成异常导致室管膜耦合缺陷、纤毛跳动不同步和室管膜剥脱，进而导致脑积水。同一足月SBA胎儿中存在不同阶段的室管膜剥脱，提示该过程在出生后仍在继续。
